Overcoming resistance

Altering microbial enzymes can lead to more powerful drugs that are effective against bacteria resistant to traditional antibiotics

By Hannah Waters | April 11, 2011

The evolution of antibiotic-resistant bacteria has left researchers scrambling to develop new, stronger antibiotics. Now researchers have successfully used a method that may allow them to keep up -- manipulate the pathways used by microbes to produce the antibacterial products from which antibiotics are derived.
The researchers used the technique to create a powerful new antibiotic that is highly effective against vancomycin-resistant Enterococcus bacteria in vitro and in mice, according to the linkurl:study;http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.556.html published online on Sunday (April 10) in Nature Chemical Biology, and they are hopeful that it can be applied to other antibiotic systems.

Vancomycin-resistant EnterococciImage: CDC

"It seems to be very exciting -- we've found an activity against the resistance strains," said linkurl:Stefano Donadio,;http://www.ktedogen.com/stefano.html the president of the antibiotic-developing company KtedoGen and Chief Scientific Officer of NAICONS who was not involved in the research. "But it's important to realize that it's just the beginning," he added. "There's still a long way to go before these can be of any benefit to human health."
Because glycopeptide antibiotics, such as vancomycin and teicoplanin, which work by inhibiting the ability of the bacterium to build cell walls, are toxic to human cells as well, they are only used as a last resort to fight bacterial infections. In the last five years, however, vancomycin use has gone up 79 percent, according to a recent linkurl:study;http://www.shea-online.org/View/ArticleId/72/Large-Veterans-Health-Administration-Study-Shows-Last-Resort-Antibiotics-Use-on-the-Rise.aspx from the Veterans Healthcare Administration, increasing the chances that bacteria will evolve resistance to the drug. Indeed, there have been many reports of vancomycin resistance among common infectious bacteria, and even in methicillin-resistant Staphylococcus aureus (MRSA), one of the leading causes of hospital-acquired bacterial infections.
linkurl:Tsung-Lin Li;http://www.genomics.sinica.edu.tw/index.php?option=com_content&view=article&id=65&Itemid=178&lang=en of Academia Sinica in Taiwan wondered if he could subtly alter the biochemical structure of glycopeptide antibiotics to boost their efficacy against the evolving bacteria. "If we understand [antibiotic] biosynthesis, we maybe can make a hybrid or manipulate a gene," Li said. "Even the most modest structural modification can overcome the resistance."
Many antibiotics used today were originally isolated from soil microbes, such as fungi and bacteria, which use the compounds to protect themselves against competing microorganisms. Studying the bacterium Nonomuraea and its natural defense product, a glycopeptide antibiotic A40926, the researchers played with the molecular machinery responsible for the compound's production to see if they could alter its effectiveness against other bacteria.
They focused on an enzyme involved in the last step of A40926 synthesis, whose structure suggested that it could be easily manipulated. By providing different building blocks, the researchers could coax the enzyme to make slightly different variations of the antibacterial compound.
Testing the variations against vancomycin-resistant Enterococcus (VRE), a gram-positive bacterium similar to MRSA, the team identified a particularly promising candidate that worked better than vancomycin or teicoplanin at reducing bacterial cell counts in vitro and in the blood of VRE-infected mice.
"They really increased the activity on organisms that are otherwise resistant to teicoplanin and vancomycin," said linkurl:Lynn Silver,;http://f1000.com/thefaculty/member/1101929217506899 an industry consultant at LL Silver Consulting who worked in antibacterial discovery for 21 years and was not involved in the research. Though whether or not the technique could be easily applied to other microbe-antibiotic systems also remains to be seen, she added. "What they've done is sort of specific, though the concept is not crazy."
It is also unclear how the antibiotics work, Donadio noted. "We don't know yet if these molecules they made act by the same or different mechanism of action than vancomycin or teicoplanin," he said. "It would have to be investigated if this compound would ever be tested in humans."
Y.C. Liu et al., "Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds," Nature Chemical Biology, doi: 10.1038/nchembio.556, 2011.**__Related stories:__*** linkurl:Opinion: 5 ways to save antibiotics;http://www.the-scientist.com/news/display/57862/ [14th December 2010]*linkurl:The Garden of Antimicrobial Delights;http://www.the-scientist.com/article/display/57352/ [1st May 2010]*linkurl:Antibiotics feed bacteria;http://www.the-scientist.com/blog/display/54522/ [3rd April 2008]

Comments

The Infectious Disease Society of America and the WHO are working very hard to salvage the remaining antibiotics. The bugs are rapidly out distancing us and the pharmaceutical industry is seemingly disinterested in new products. While this is going on, every sewer plant in the U.S. is spewing out antibiotic resistant microbes and their genetic material, the antibiotic resistant genes (ARGs). The US/EPA which controls the functioning of sewer plants has been aware of this for about three decades and had done essentially nothing about it. In conversations with CDC they tell me that there is no focus on sewer plant generated antibiotic resistance. The Inter Agency Task Force on Antibiotic Resistance indicated, when I recently talked to them, that they had not even thought along these lines.\n\nSewer plants discharge copious amounts of ARGs into America's rivers. The next down-stream city takes these into its raw water stock for drinking water. ARGs are now found in the nation's drinking water supply. Chlorine and UV have little effect on ARGs and they are so small that they pass through most filtering systems now in use.\n\nSo, we come up with new drugs, expose the bugs to new challenges, bring them all together in a sewer plant for gene exchange and we dump the offending bacteria right back into the environment, then we race to make new drugs and go into the sewer, more gene transfer, we dump more bugs into the environment. Doesn't make a lot of sense, but then that's politics.\n\nDr Edo McGowan, Medical Geo-hydrology